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Instrumental activities of daily living (IADLs) are used to diagnose older adults as having mild cognitive impairment (MCI) versus dementia. IADL rating scales, however, can be subject to biases. These biases, known as differential item functioning (DIF), occur when individuals receive different ratings based on demographic or contextual factors. Evaluating and addressing DIF is crucial because of the impact of IADL ratings on eligibility for clinical trials and access to FDA approved treatments. The Functional Activities Questionnaire (FAQ), an informant IADL rating scale, was available for 7,958 participants with MCI in the National Alzheimer's Coordinating Center Uniform Data Set. Data were analyzed using the Likelihood-based Investigation of Differential Item Functioning (LIDIF) model. This multivariate approach evaluates uniform and non-uniform DIF while simultaneously adjusting for multiple covariates, including participants' age, sex, education, race, and informants' sex and cohabitation status in a multivariate setting. DIF-adjusted IADL levels were estimated using posterior means to mitigate rating biases RESULT: Significant DIF effects were identified across all 10 FAQ items, with race and informant characteristics emerging as key sources of bias. Black participants were consistently rated as less impaired than white participants, particularly at higher impairment levels, even after adjusting for age, education, and other covariates. This was most pronounced for items related to paying bills, shopping, games, meal preparation, paying attention, remembering appointments and travelling. Informants' cohabitation status also influenced ratings, with non-cohabitating informants generally reporting less functional impairment compared to cohabitating informants. FAQ total scores underestimated impairment in Black participants due to a strong floor effect, where a large proportion of individuals received the lowest possible scores. DIF-adjusted IADL estimates reduced racial disparities, mitigated floor effects, and identified a greater number of individuals with impairment. These findings highlight the importance of accounting for demographic and informant-related characteristics in FAQ assessment. Adjusting for these biases improves the accuracy and fairness of IADL assessments, supporting equitable clinical decision-making and ensuring that functional impairment is appropriately recognized across diverse populations.

Background Instrumental activities of daily living (IADLs) are used to diagnose older adults as having mild cognitive impairment (MCI) versus dementia. IADL rating scales, however, can be subject to biases. These biases, known as differential item functioning (DIF), occur when individuals receive different ratings based on demographic or contextual factors. Evaluating and addressing DIF is crucial because of the impact of IADL ratings on eligibility for clinical trials and access to FDA approved treatments. Method The Functional Activities Questionnaire (FAQ), an informant IADL rating scale, was available for 7,958 participants with MCI in the National Alzheimer's Coordinating Center Uniform Data Set. Data were analyzed using the Likelihood‐based Investigation of Differential Item Functioning (LIDIF) model. This multivariate approach evaluates uniform and non‐uniform DIF while simultaneously adjusting for multiple covariates, including participants’ age, sex, education, race, and informants’ sex and cohabitation status in a multivariate setting. DIF‐adjusted IADL levels were estimated using posterior means to mitigate rating biases Result Significant DIF effects were identified across all 10 FAQ items, with race and informant characteristics emerging as key sources of bias. Black participants were consistently rated as less impaired than white participants, particularly at higher impairment levels, even after adjusting for age, education, and other covariates. This was most pronounced for items related to paying bills, shopping, games, meal preparation, paying attention, remembering appointments and travelling. Informants’ cohabitation status also influenced ratings, with non‐cohabitating informants generally reporting less functional impairment compared to cohabitating informants. FAQ total scores underestimated impairment in Black participants due to a strong floor effect, where a large proportion of individuals received the lowest possible scores. DIF‐adjusted IADL estimates reduced racial disparities, mitigated floor effects, and identified a greater number of individuals with impairment. Conclusion These findings highlight the importance of accounting for demographic and informant‐related characteristics in FAQ assessment. Adjusting for these biases improves the accuracy and fairness of IADL assessments, supporting equitable clinical decision‐making and ensuring that functional impairment is appropriately recognized across diverse populations.

Background Redox signaling, which can be assessed by circulating aminothiols, reflects oxidative stress (OS) status and has been linked to clinical cardiovascular disease and its risk factors. These, in turn, are related to executive function decline. OS may precede the pro-inflammatory state seen in vascular disease. The objective of this study is to investigate the association between aminothiol markers of OS and inflammation in cognitive decline, especially in the executive cognitive domain which is highly susceptible to cardiovascular risk factors and is an important predictor of cognitive disability. Methods The study design is that of a longitudinal cohort study within the setting of a large academic institution with participants being university employees ( n  = 511), mean age 49 years, 68% women, and 23% African-American. These participants were followed for four consecutive years with a yearly cognitive assessment conducted using computerized versions of 15 cognitive tests. Peripheral cystine, glutathione, their disulfide derivatives, and C-reactive protein (CRP) were measured. Results Lower levels of glutathione at baseline was associated with a decline in the executive domain over 4 years (covariate-adjusted relative risk (RR) for glutathione = 1.70 (95% CI = 1.02–2.85), p  = 0.04). Furthermore, a longitudinal decline in glutathione level was associated with a faster decline in the executive domain ( p  = 0.03). None of the other OS markers or CRP were linked to cognitive decline over 4 years. Conclusion Increased OS reflected by decreased glutathione was associated with a decline in executive function in a healthy population. In contrast, inflammation was not linked to cognitive decline. OS may be an earlier biomarker that precedes the inflammatory phase of executive decline with aging.

Objective:Compensatory strategy training has been identified as a useful mechanism to improve everyday cognitive function among older adults with Mild Cognitive Impairment (MCI). Despite this, few studies have looked at cognitive factors that support adherence and engagement in these programs, which are key to maximizing benefit. The present study aimed to evaluate the relationship between cognition, adherence, and engagement during a group-based compensatory strategy training for people with MCI. We hypothesized individuals with better memory and executive function performance would show better adherence and higher engagement scores in cognitive training classes.Participants and Methods:Twenty-five participants enrolled in Emory University's Charles and Harriet Schaffer Cognitive Empowerment Program (CEP) completed an 11-week compensatory strategy training group (CEP-CT). CEP-CT is adapted from Ecologically Oriented Neurorehabilitation to be suitable for people with MCI. Participants enrolled were on average 74.3 years old (SD= 5.4), 52% Male, primarily Caucasian (80%; 16% African American), and college educated (M= 16.5 years; SD= 2.7). All participants received clinical diagnoses of MCI prior to enrollment in the program. Participants completed multiple cognitive measures, including Montreal Cognitive Assessment (MoCA), Hopkins Verbal Learning Test (HVLT), Trail Making Test A & B (TMT), Number Span Forward (NSF) and verbal fluency (S-words and Animals). For all group sessions, class attendance (present vs. not present) was recorded for each participant and their care partner, and engagement ratings for participants were recorded by the facilitator on a 1 to 5 scale (higher scores indicate better engagement). Outcomes include adherence to cognitive training (percentage of sessions attended; M= 82% class attendance, SD= 18%) as well as the average engagement ratings across 11 weeks (M= 3.25, SD= .40).Results:Bivariate Pearson correlations revealed that individuals who attended more classes also demonstrated better engagement in class, r= .44, p= .03. Class attendance was significantly related to performance on measures of memory and executive function (HVLT: r= -.42, p= .04; TMT-B: r= .69, p= .04), such that participants who performed worse on these measures attended more CEP-CT classes. Average engagement ratings were unrelated to cognitive performance.Conclusions:Results did not support initial hypotheses, and instead indicate individuals with poorer performance on measures of memory and executive function had better adherence to CEP-CT classes, as measured by attendance. These results may indicate individuals experiencing cognitive difficulties are more likely to attend cognitive training classes. Subjective engagement ratings were unrelated to cognition; however, individuals who attended more sessions were more engaged in cognitive training classes. Future areas of research include objective measurement of class engagement as well as the incorporation of nuanced adherence metrics to further elucidate the relationship between these factors and cognition in MCI.

Introduction Advances in natural language processing (NLP), speech recognition, and machine learning (ML) allow the exploration of linguistic and acoustic changes previously difficult to measure. We developed processes for deriving lexical‐semantic and acoustic measures as Alzheimer's disease (AD) digital voice biomarkers. Methods We collected connected speech, neuropsychological, neuroimaging, and cerebrospinal fluid (CSF) AD biomarker data from 92 cognitively unimpaired (40 Aβ+) and 114 impaired (63 Aβ+) participants. Acoustic and lexical‐semantic features were derived from audio recordings using ML approaches. Results Lexical‐semantic (area under the curve [AUC] = 0.80) and acoustic (AUC = 0.77) scores demonstrated higher diagnostic performance for detecting MCI compared to Boston Naming Test (AUC = 0.66). Only lexical‐semantic scores detected amyloid‐β status (p = 0.0003). Acoustic scores associated with hippocampal volume (p = 0.017) while lexical‐semantic scores associated with CSF amyloid‐β (p = 0.007). Both measures were significantly associated with 2‐year disease progression. Discussion These preliminary findings suggest that derived digital biomarkers may identify cognitive impairment in preclinical and prodromal AD, and may predict disease progression. Highlights This study derived lexical‐semantic and acoustics features as Alzheimer's disease (AD) digital biomarkers. These features were derived from audio recordings using machine learning approaches. Voice biomarkers detected cognitive impairment and amyloid‐β status in early stages of AD. Voice biomarkers may predict Alzheimer's disease progression. These markers significantly mapped to functional connectivity in AD‐susceptible brain regions.

Importance Differences in cerebrospinal fluid (CSF) tau Alzheimer dementia (AD) biomarkers by self-identified race have been observed in prior studies. More recently, plasma biomarkers have been gaining recognition, but whether they exhibit similar differences is unclear. Furthermore, the underlying explanation for these differences in AD biomarkers is still unexplored. Objectives To investigate differences in plasma biomarkers by race and genetic ancestry and explore potential underlying explanations for these differences. Design, Setting, and Participants This cross-sectional study used participant data from the Brain, Stress, Hypertension, and Aging Research Program (B-SHARP), an observational study conducted in the greater Atlanta metropolitan area. Participants were enrolled from March 1, 2016, to January 1, 2020. Main Outcomes and Measures Main outcomes were plasma and CSF amyloid-β (Aβ) 42, Aβ40, phosphorylated tau181(p-tau181), and neurofilament light. General linear models were used for key comparisons. Exposures Main independent variables were self-identified race and genetic ancestry. Additional variables were cardiovascular factors,APOE4, educational attainment, Area Deprivation Index, and C-reactive protein (reflecting systemic inflammation state). Results This analysis included 617 participants (mean [SD] age, 66 [7.9] years; 300 [49%] African American and 317 [51%] White; 429 [70%] with mild cognitive impairment). On the basis of self-reported race, plasma levels of Aβ42 (adjusted mean difference, −1.20 pg/mL; 95% CI, −2.33 to −0.07 pg/mL), Aβ40 (adjusted mean difference, −37.78 pg/mL; 95% CI, −60.16 to −15.39 pg/mL), p-tau181(adjusted mean difference, −4.66 pg/mL; 95% CI, −7.05 to −1.90 pg/mL), and neurofilament light (adjusted mean difference, −1.58; 95% CI, −2.83 to −0.19 pg/mL) were consistently lower in African American individuals after adjusting for demographic characteristics, educational attainment, cognition,APOE4, and cardiovascular factors. A similar pattern was observed in the CSF biomarkers except for Aβ42 and Aβ40. Although unadjusted analyses revealed an association between these biomarkers and African ancestry, these associations were not significant after adjusting for the same covariates. Differences by self-reported race were not explained by varied cardiovascular risk factors, C-reactive protein, educational attainment, or Area Deprivation Index. Conclusions and Relevance In this cross-sectional study of plasma biomarkers by race and genetic ancestry, the results indicated that plasma p-tau181, Aβ40, and NFL were lower in African American individuals based on self-reported race but not genetic ancestry. These differences were not explained by cardiovascular risks or clinical stage differences. These racial differences should be considered in clinical interpretations and clinical trial screenings to avoid an additional increase in underrepresentation of African American individuals in AD trials.

Self- and informant-ratings of functional abilities are used to diagnose mild cognitive impairment (MCI) and are commonly measured in clinical trials. Ratings are assumed to be accurate, yet they are subject to biases. Biases in self-ratings have been found in individuals with dementia who are older and more depressed and in caregivers with higher distress, burden, and education. This study aimed to extend prior findings using an objective approach to identify determinants of bias in ratings. Participants were 118 individuals with MCI and their informants. Three discrepancy variables were generated including the discrepancies between (1) self- and informant-rated functional status, (2) informant-rated functional status and objective cognition (in those with MCI), and (3) self-rated functional status and objective cognition. These variables served as dependent variables in forward linear regression models, with demographics, stress, burden, depression, and self-efficacy as predictors. Informants with higher stress rated individuals with MCI as having worse functional abilities relative to objective cognition. Individuals with MCI with worse self-efficacy rated their functional abilities as being worse compared to objective cognition. Informant-ratings were worse than self-ratings for informants with higher stress and individuals with MCI with higher self-efficacy. This study highlights biases in subjective ratings of functional abilities in MCI. The risk for relative underreporting of functional abilities by individuals with higher stress levels aligns with previous research. Bias in individuals with MCI with higher self-efficacy may be due to anosognosia. Findings have implications for the use of subjective ratings for diagnostic purposes and as outcome measures.

The impact of COVID-19 severity on development of long-term sequelae remains unclear, and symptom courses are not well defined. This ambidirectional cohort study recruited adults with new or worsening symptoms lasting ≥3 weeks from confirmed SARS-CoV-2 infection between August 2020-December 2021. COVID-19 severity was defined as severe for those requiring hospitalization and mild for those not. Symptoms were collected using standardized questionnaires. Multivariable logistical regression estimated odds ratios (OR) and 95% confidence intervals (CI) for associations between clinical variables and symptoms. Of 332 participants enrolled, median age was 52 years (IQR 42-62), 233 (70%) were female, and 172 (52%) were African American. Antecedent COVID-19 was mild in 171 (52%) and severe in 161 (48%). In adjusted models relative to severe cases, mild COVID-19 was associated with greater odds of fatigue (OR:1.83, CI:1.01-3.31), subjective cognitive impairment (OR:2.76, CI:1.53-5.00), headaches (OR:2.15, CI:1.05-4.44), and dizziness (OR:2.41, CI:1.18-4.92). Remdesivir treatment was associated with less fatigue (OR:0.47, CI:0.26-0.86) and fewer participants scoring >1.5 SD on PROMIS Cognitive scales (OR:0.43, CI:0.20-0.92). Fatigue and subjective cognitive impairment prevalence was higher 3-6 months after COVID-19 and persisted (fatigue OR:3.29, CI:2.08-5.20; cognitive OR:2.62, CI:1.67-4.11). Headache was highest at 9-12 months (OR:5.80, CI:1.94-17.3). Mild antecedent COVID-19 was associated with highly prevalent symptoms, and those treated with remdesivir developed less fatigue and cognitive impairment. Sequelae had a delayed peak, ranging 3-12 months post infection, and many did not improve over time, underscoring the importance of targeted preventative measures.

Vascular dysfunction has emerged as a potential early contributor to AD/ADRD pathophysiology, highlighting the need for accessible biomarkers to support early detection and interventions. Arterial stiffening may contribute to cerebral microvascular damage and the accumulation of white matter hyperintensities (WMH), a neuroimaging marker associated with AD/ADRD. While cerebrospinal fluid (CSF) biomarkers such as Aβ42/tTau index (ATI) indicate AD/ADRD pathology, the additive value of vascular measures remains unclear. This study investigated whether pulse pressure (PP), a proxy of arterial stiffness, is associated with WMH independently of CSF biomarkers in healthy older adults. 394 cognitively healthy older adults (age: 62.6±6.6 yrs; 69.7% female; 15.0% African American) from the Emory Healthy Brain Study underwent MRI, lumbar puncture, and blood pressure assessments. PP was calculated as the difference between brachial systolic and diastolic pressure. ATI was calculated from CSF concentrations of Aβ42 and total Tau. Hierarchical linear regression examined the independent contributions of PP and ATI to WMH volume. Covariates (age, sex, education, BMI, race, and mean arterial pressure) were included in step 1, PP and ATI in step 2, and race and age group (older: >62.5, younger: ≤62.5 yrs) interactions in step 3. Bivariate analyses revealed PP was positively associated with WMH (r=0.293, p<0.001) while ATI was inversely associated with WMH (r=-0.194, p<0.001). After adjusting for covariates, PP was non-significantly associated with WMH (β=0.051, p=0.314), while ATI was negatively associated (β=-0.091, p=0.031). These associations were modified by age stratification and race. The association between PP and WMH was weaker in younger adults (older: B=0.009, younger: B=0.001, p=0.016) and African Americans (African American: B=-0.016, non-African American: B=0.001, p=0.010). Similarly, the relationship between ATI and WMH was weaker in younger adults (older: B=-0.187, younger: B=0.056, p=0.001) but did not vary by race (p=0.794). Arterial stiffness may complement CSF biomarkers in characterizing WMH burden-a marker linked to AD/ADRD. The moderating effects of age and race highlight the need for precision approaches in assessing vascular contributions to dementia risk. Given the routine nature of blood pressure assessments, PP may serve as a scalable tool for early risk stratification in aging and dementia research.

Background Vascular dysfunction has emerged as a potential early contributor to AD/ADRD pathophysiology, highlighting the need for accessible biomarkers to support early detection and interventions. Arterial stiffening may contribute to cerebral microvascular damage and the accumulation of white matter hyperintensities (WMH), a neuroimaging marker associated with AD/ADRD. While cerebrospinal fluid (CSF) biomarkers such as Aβ42/tTau index (ATI) indicate AD/ADRD pathology, the additive value of vascular measures remains unclear. This study investigated whether pulse pressure (PP), a proxy of arterial stiffness, is associated with WMH independently of CSF biomarkers in healthy older adults. Methods 394 cognitively healthy older adults (age: 62.6±6.6 yrs; 69.7% female; 15.0% African American) from the Emory Healthy Brain Study underwent MRI, lumbar puncture, and blood pressure assessments. PP was calculated as the difference between brachial systolic and diastolic pressure. ATI was calculated from CSF concentrations of Aβ42 and total Tau. Hierarchical linear regression examined the independent contributions of PP and ATI to WMH volume. Covariates (age, sex, education, BMI, race, and mean arterial pressure) were included in step 1, PP and ATI in step 2, and race and age group (older: >62.5, younger: ≤62.5 yrs) interactions in step 3. Results Bivariate analyses revealed PP was positively associated with WMH (r=0.293, p<0.001) while ATI was inversely associated with WMH (r=‐0.194, p<0.001). After adjusting for covariates, PP was non‐significantly associated with WMH (β=0.051, p=0.314), while ATI was negatively associated (β=‐0.091, p=0.031). These associations were modified by age stratification and race. The association between PP and WMH was weaker in younger adults (older: B=0.009, younger: B=0.001, p=0.016) and African Americans (African American: B=‐0.016, non‐African American: B=0.001, p=0.010). Similarly, the relationship between ATI and WMH was weaker in younger adults (older: B=‐0.187, younger: B=0.056, p=0.001) but did not vary by race (p=0.794). Conclusion Arterial stiffness may complement CSF biomarkers in characterizing WMH burden‐a marker linked to AD/ADRD. The moderating effects of age and race highlight the need for precision approaches in assessing vascular contributions to dementia risk. Given the routine nature of blood pressure assessments, PP may serve as a scalable tool for early risk stratification in aging and dementia research.